ATM safeguards liver homeostasis by mitigating mitochondrial hypermetabolism and bioenergetic crisis in MASLD.

The rising incidence of Metabolic dysfunction-associated steatotic liver disease (MASLD) and its progressive stage, Metabolic dysfunction-associated steatohepatitis (MASH), represents the most prevalent chronic liver condition and a major health problem. Key molecular mechanisms driving this progression remain unclear. We demonstrate that Replication stress (RS) is a dominant hallmark across all stages of human MASLD, while an ATM-mediated DNA Damage Response (DDR) signature is specifically associated with advanced, fibrosing MASH. Using a preclinical MASLD model, we show that ATM (Ataxia-Telangiectasia Mutated) serves as a critical metabolic safeguard. Hepatocyte-specific deletion of ATM significantly worsens liver damage and fibrosis. Mechanistically, ATM-deficient MASLD hepatocytes exhibit increased oxygen consumption and accelerated TCA cycle flux, driving a metabolic surge accompanied by proton leak, ROS production and mitophagy. This mitochondrial dysfunction results in severe hepatic nucleotide pool imbalance, energy deficit and toxic lipid accumulation. Together, these findings reveal that, beyond its canonical role in DNA repair, ATM safeguards liver homeostasis by restraining mitochondrial hypermetabolism and preventing bioenergetic crisis during MASLD progression.